Etanercept reduces neuroinflammation and lethality in mouse model of Japanese encephalitis

J Infect Dis. 2014 Sep 15;210(6):875-89. doi: 10.1093/infdis/jiu179. Epub 2014 Mar 20.


Background: Japanese encephalitis virus (JEV) is a neurotropic flavivirus that causes Japanese encephalitis (JE), which leads to high fatality rates in human. Tumor necrosis factor alpha (TNF-α) is a key factor that mediates immunopathology in the central nervous system (CNS) during JE. Etanercept is a safe anti-TNF-α drug that has been commonly used in the treatment of various human autoimmune diseases.

Methods: The effect of etanercept on JE was investigated with a JEV-infected mouse model. Four groups of mice were assigned to receive injections of phosphate-buffered saline, etanercept, JEV, or JEV plus etanercept. Inflammatory responses in mouse brains and mortality of mice were evaluated within 23 days post infection.

Results: The in vitro assay with mouse neuron/glia cultures showed that etanercept treatment reduced the inflammatory response induced by JEV infection. In vivo experiments further demonstrated that administration of etanercept protected mice from JEV-induced lethality. Neuronal damage, glial activation, and secretion of proinflammatory cytokines were found to be markedly decreased in JEV-infected mice that received etanercept treatment. Additionally, etanercept treatment restored the integrity of the blood-brain barrier and reduced viral load in mouse brains.

Conclusions: Etanercept effectively reduces the inflammation and provides protection against acute encephalitis in a JEV-infected mouse model.

Keywords: Japanese encephalitis virus; TNF-α; etanercept; inflammation; viral encephalitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / pathology
  • Blotting, Western
  • Brain / metabolism
  • Brain / pathology
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Disease Models, Animal
  • Encephalitis Virus, Japanese / metabolism
  • Encephalitis, Japanese / drug therapy*
  • Encephalitis, Japanese / pathology
  • Etanercept
  • Immunoglobulin G / therapeutic use*
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Inbred BALB C
  • Neuroglia / pathology
  • Receptors, Tumor Necrosis Factor / therapeutic use*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*


  • Cytokines
  • Immunoglobulin G
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Etanercept